Cardiovascular disorders often are the primary abnormalities in multisystem disease. Intracardiac tumors, including atrial myxomas, are significant causes of stroke and heart failure and may present as heritable systemic disorders. The Carney complex is an autosomal dominant syndrome in which intracardiac myxomas, arise in the setting of cutaneous hyperpigmentaton and lentiginosis along with less common extracardiac myxomas as well as endocrinopathy. Investigation of genetic diseases, such as Carney complex, yields important insights into disease pathophysiology as well as normal physiology. Molecular genetic techniques can be used to study kindreds affected by Carney complex in order to identify the mutated disease gene in this syndrome. Our preliminary investigation demonstrated genetic heterogeneity of this syndrome and now has defined a novel 13 cM locus on the long arm of chromosome 17 that, with odds of 6 trillion: 1, contains the Carney complex disease gene in at least four families. In this application, we propose to identify the Carney complex disease gene on chromosome 17q and the mutations in this gene that cause intracardiac myxomas. New microsatellites and haplotype analysis will be used to refine the l7q Carney complex locus (CAR) genetic map and to assemble a genomic clone contig of the region. In addition, loss of heterozygosity analysis of cultured myxoma tumor cells will be employed to reduce further the genetic and physical interval containing CAR. Physical mapping of the interval will be performed by establishing YAC and other large insert genomic clone contigs of the CAR locus. Known genes will be assayed to determine if they map to the CAR locus by PCR and southern blot analysis of the genomic clone contigs. Novel transcripts at the CAR locus will be isolated by exon trapping and cDNA selection studies. Candidate genes and transcripts that do map to this locus will then be evaluated for mutations to identify the Carney complex disease gene. Structural analysis of the Carney complex gene and its associated mutations will foster new concepts of mechanisms underlying neoplastic transformation as well as normal growth homeostasis in the heart and other tissues. Increased understanding of the regulation of cardiac cell growth will improve diagnosis and treatment of intracardiac myxomas and will also suggest novel approaches to stimulate cardiac remodeling that can contribute to the management of the myopathic and ischemic heart.